Cardiovascular disease is the major cause of morbidity and mortality in the United States. While varied in clinical presentation, it is generally assumed that inflammation is a common mechanism of cardiovascular disease pathogenesis. The vascular endothelium is the structural lining of all blood vessels that serves as an active barrier between the circulation and the surrounding tissue, and are increasingly recognized for vital participant in the inflammatory signaling cascade. A common mechanism by which endothelial cells (ECs) sense inflammatory signals is by an increase in intracellular calcium (Ca2+) via inositol 1,4,5-trisphosphate receptors (InsP3R) on the endoplasmic reticulum. Despite their ubiquitous presence in the vasculature, ECs display a great degree of heterogeneity in the InsP3R -mediated Ca2+ response dependent upon their vascular origin. Unfortunately, how heterogeneous Ca2+ signals are generated and how they impact endothelial function are unknown. The focus of my work has been to understand the delicate interaction between Ca2+ signals and mitochondria! function, and how this interaction impacts endothelial homeostasis. Recently, I have discovered that InsPSR -mediated Ca2+ transmits to the mitochondria, which 'decodes' these Ca2+ signals into reactive oxygen species (ROS) and endothelial inflammation. My preliminary findings suggest that ROS may selectively modify InsPSRs to mediate intracellular Ca2+ signaling. The short term goal of this project (K.99) is to investigate whether heterogeneous Ca2+ signaling is due to the selective modification of InsP3R type 1 and 2 in ECs. Under the mentorship of Drs. Aron Fisher and Madesh Muniswamy, the initial phase of this award will allow me to study the control of EC Ca2+ signaling by ROS, and also to provide me with the direction, laboratory facilities, and scientific structure necessary to advance my skills and transition into an independent investigator. The long term goal of this work (ROO) is to ultimately understand how mitochondrial ROS impacts EC Ca2+ signaling and triggers inflammatory signaling via the transcription factor NF-kB. While a correlative link between mitochondrial function, ROS production, and EC inflammation exists, a causative link between these variables has not been established. If a definitive link can be made, agents designed to counter specific InsPSR activity and mitochondrially-targeted antioxidant compounds may constitute an attractive therapeutic target during vascular inflammatory conditions. (End of Abstract)